Rats come in a side variety of colors and patterns, from solid
black to white, from dark browns to warm tans to creams, from slate
grey to pale blue. Rats can display patches of white that range from
a small chest spot to a belly blotch to white with a pigmented head
and beyond. The variation is immense! Where do these coat colors and
patterns come from? How are the different pigments made and
integrated into the growing fur? How do mutations along the pigment
production pathway produce the different colors we see in rats?

Disclaimer: I am a biologist, not a rat breeder, and my
interest in rat colors stems from my fascination with the biology of
pigmentation. Therefore, this is not an article about rat
standards! If you are seeking rat color standards, descriptions, and
their associated Mendelian notations, check out one of the many
websites of fancy rat organizations such as AFRMA,
RMFE,
NFRS, and AusRFS
to name just a few.

Not all rat colors are included here because I have focused my
attention on the mutations whose cellular consequences are known.
There are many other colors whose specific causes are not yet
known.

A word about color names... I have occasionally included color
names for purposes of illustration. Note, however, that such color
names may vary between rat organizations and countries. The same
color may be called by different names; a particular name may refer
to different colors, depending on who you talk to. Lastly, a
particular color may have a number of possible underlying causes, so
use caution when extrapolating from this document to your pet rats.
By and large, I have tried to steer clear of "official" color names
and rat standards, and have instead focused on my area of interest:
the biology of pigmentation.

A Pigment
Primer

Pigments are made in cells called melanocytes. During
development of the embryo, the cells that will become melanocytes
(these precursors are called melanoblasts) migrate from the
dorsal area -- from an active region running along the back of the
embryo called the neural crest -- to the rest of the body.
These cells take up positions at the base of hair follicles. They
also become integral parts of other organs such as the eye, inner
ear, and other neural systems (Figure 1). If the migration of these
cells is disrupted, then some areas of the body won't have
melanocytes, and these areas of the body will produce white
hairs.

The melanoblasts differentiate into melanocytes, which live in the
skin and at the base of each hair, and produce melanin pigments. The
menanin pigment particles, called granules, are incorporated into the
growing hair (Figure 2).

Figure 2. Cross-section of a hair and follicle.
Melanocytes synthesize melanin granules which are incorporated into the
growing hair (click on image for larger picture).

Inside the melanocyte...

Pigment particles, called granules, are synthesized in little
vesicles inside melanocytes. These vesicles are called
melanosomes. Two types of pigment are produced in melanosomes:
yellow-red pigments called phaeomelanins and brown-black
eumelanins.

There are actually separate melanosomes for the two types of
pigment. Phaeomelanosomes specialize in making the yellow-red
phaeomelanins. Eumelanosomes specialize in making the
brown-black eumelanins.

A melanocyte may switch between producing pale and dark pigments
in a single hair. In this case the effect is banded hairs, as seen in
the agouti allele.

Melanosomes produce pigments inside the melanocyte. Melanosomes
start their journey in the middle of the melanocyte cell, and migrate
to the outer edge of the cell, through projections called
dendrites (Figure 3).

[Melanocytes are actually a type of neural cell, coming from
the neural crest, so they have some neuron-like properties such as
dendrites].

At the outer edge of the cell, melanosomes release their pigment,
which is then incoporated into the surrounding keratinocytes and the
shaft of the growing hair.

Figure 3. Melanocytes contain melanosomes:
phaeomelanosomes and eumelanosomes, which synthesize pale and dark
pigments. Switching between pale and dark pigment production on a
single hair produces banded hairs, called agouti.
Melanosomes migrate to the base of the dendrites. From there they are
transported to the dendrite tips. Disorders in melanosome
formation in rats include red-eyed dilution.

How do melanosomes migrate from the middle to the edge of the
melanocyte? Melanosomes are actually attached to a framework of
microtubules, and are transported up the dendrites on ladders
of actin. The little "feet" that walk up the actin fibers are called
myosin 5 (Figure 4).

Figure 4. Melanosomes are attached to a branching
microtubule arbor inside the melanocyte. To move up the dendrite, they
attach to actin filaments with myosin 5, and the myosin 5 "walks" them
to the cell edge (click on image for larger picture). Disorders in melanosome transport include the dilution allele.

Inside the melanosome...

Inside the melanosomes, mammals make two kinds of pigments:
eumelanins, which range from dark brown to black, and
phaeomelanins which range from red to yellow.

Both types of pigment are made from the same starting product, the
amino acid tyrosine, and the first several steps of their
production are the same.

The enzyme tyrosinase (coded by a gene called
chinchilla) converts tyrosine, which is colorless, into
dopaquinone, also colorless. Phaeomelanins are made out of these.

To make eumelanin, dopaquinone is converted into dopachrome.
Dopachrome can take two pathways to eumelanin. In the first pathway,
dopachrome is converted into 5,6 dihydroxyindole, which is brown, and
then into complex quinone compounds by the enzyme tyrosinase
related protein I (TYRP1, produced by the brown gene). In
the second pathway it is converted into DHCA by dopachrome
tauromerase (DCT) and from there to complex quinones by TYRP1
again. Complex quinones are then polymerized into eumelanin, which is
black (Figure 5).

Figure 5. Simplified synthesis of the melanins phaeomelanin
and eumelanin. Disorders in pigment
synthesis include chinchilla
(codes tyrosinase) and brown(codes
TYRP1). (click on image for larger picture). The tradeoff between
synthesis of phaeomelanin and eumelanin along the shaft of a growing
hair is mediated by the agouti allele.

Phaemelanosomes and eumelanosomes are actually quite different
inside. Phaeomelanosomes are spherical in shape and are quite
primitive, lacking TRP1, TRP2, and p-protein (seen in pink-eyed
dilution). They have only one third the level of tyrosinase
as eumelanosomes.

Eumelanosomes are more sophisticated, oval-shaped melanosomes,
which have TRP1, TRP2, p-protein, and three times the tyrosinase as
phaeomelanosomes.

Conclusion

Variations in hair color can arise from differences in synthesis
of pigment, resulting in black, brown, yellow or colorless pigment
granules, or in deposit of pigment in the hair shaft. Differences in
pigment deposit in the hair produce variation in the intensity and
shade of the color. The color and amount of granules can vary along
the length of a single hair, or between different hairs. Variation in
pigmentation comes from patterns of melanocyte migration and final
distribution. Areas with melanocytes become pigmented, but areas
without melanocytes produce depigmented, white hairs.

In the next sections I'll examine many different mutations
occuring along this pathway, and how these mutations give rise to the
final coat color. I'll also examine other "side" effects of these
mutations, and possible parallels found in human pigmentation.

In the embryo, a fold develops down the back called the neural
tube, which contains an active region called the neural
crest. This region supplies the pigment cells
(melanocytes)
that migrate all over the body.

Specifically, the pigment cells migrate to pairs of specific sites
on either side of the body as well as the backline. There are three
such sites on the head (near the eye, near the ear, and near the top
of the head), and six sites along each side of the body, and several
along the tail. A few pigment cells migrate to each of these sites,
where they proliferate and migrate outwards, joining up to form
larger patches, spreading down the legs and down the head until they
meet up under the chin, and down the body until they meet up on the
belly (Cattanach 1999).

Once the pigment cells have finished migrating they take up
positions at the base of hair follicles. There they synthesize
melanin pigment, and feed it into the growing hair. Normally, all
follicles have pigment cells associated with them and all the
animal's fur is pigmented. But if no pigment cells are associated
with a follicle, there is no pigment in that hair. Mutations that
affect pigment cell distribution during the development of the embryo
determine which parts of the body have pigment cells, and hence
produce pigment, and which parts have no pigment cells and produce
depigmented hairs.

Pigment cells also migrate to the iris and retina of the eye. If
the iris does not have pigment cells, it looks red (in rats and mice)
or blue (dogs and cats). Odd-eyed rats are caused by the migration of
pigment cells to one eye but not the other. (Note: the white coat and
red eyes of albinos are not caused by a
failure of pigment cell migration, but by the inability of pigment
cells to produce pigment).

Pigment cells migrate to the inner ear too (cochlea and stria
vascularis), where they play an undefined but essential role in
maintaining hearing. If the inner ear does not have pigment cells,
the individual may be deaf.

Pigment cells also migrate to the brain, to areas such as the
substantia nigra (part of the midbrain that regulates mood, produces
dopamine, and controls voluntary movement), the locus ceruleus (part
of the brain that deals with the stress response) as well as other
areas such as the leptomeninges (membranes surrounding the brain),
the dorsal root ganglia, and the cranial ganglia. The failure of
pigment cells to reach these areas can have a wide variety of
effects, such as a movement disorder (e.g. seizures), and diverse
effects on behavior and the individual's response to stress.

Pigment cells are therefore implicated in areas of the brain
related to mood and the stress response. This connection between
depigmentation and behavior probably played a role in animal
domestication. By selecting for tameness, breeders selected for a
different pigment cell migration in the developing nervous system,
leading to calmer animals. A side effect of this selection for
behavior was the change in pigment cell migration in the skin,
leading to a piebald coat. Piebaldness and associated docility are
found in many different domesticated species (horses, cows, dogs,
cats, birds). In fact, selection of wild animals for tame behavior
leads to depigmented areas on the fur, as shown in foxes (Belyaev
1979, Trut 1999) and rats (Trut et al. 1997). Note, however,
that if depigmentation is extreme, the animal may have neurological
impairments (Grandin 1998). Here's more on coat
color, temperament and domestication.

Pigment cells aren't the only cells that migrate from the neural
crest. Neural cells that enervate the intestines make the migration
too. If the necessary neural cells don't reach the end of the
intestine, the animal's intestines may not fuction properly,
rendering the animal unable to pass feces, which results in megacolon.

There are many mutations that may affect the migration of cells
from the neural crest. Each mutation is different, each may be
modified by other genes. Each mutation may have a constellation of
effects (pleiotropic effects) on coat color, behavior, and
sensory function. This is why white coloration, eye color anomalies,
deafness, and megacolon are often found together. They are all the
result of a delay in cell migration from the neural crest.

The hooded allele

The hooded allele in the rat delays the migration of
melanocytes from the neural crest (Figure 1). Consequently, the areas
furthest from the dorsal midline -- feet, chest, belly -- don't have
melanocytes, and those areas produce depigmented, white hair.

Figure 1. Normal and hooded rat fetuses, showing the
days on which melanoblasts reach the epidermis. Hooded rats experience
a delay in pigment cell migration (Searle 1968, from Wendt-Wagener 1961)

Click on the image to get a larger view.

H = normal, fully pigmented coat

h = piebald (hooded)

There are many different hooded alleles which cause different
degrees of delay in melanocyte migration: e.g. h(re) (restricted,
homozygous lethal), h(i) (Irish), h(n) (notch, or capped), h(e)
(extreme), which produce variable amounts of depigmentation (Robinson
1989).Other genes influence the exact layout of the
depigmented areas (Curtis & Dunning 1951), such as the hood
modifier locus h(l) for a long dorsal stripe and h(s) for a short
one.

Examples: Rats with HH have normal
pigment distribution covering their entire bodies, rats with
Hh are partially depigmented (white belly and pigmented
sides), known as berkshire, and hh rats are
hooded (pigmented head and dorsal stipe, white body).

Human analogues: The mildest analog of the
hooded gene is the piebald gene in humans. Piebald humans have a
white forelock, no pigment on the middle of the forehead, and other
patches of depigmentation elsewhere on their bodies.

Spotting lethal and white spotting
genes

Neural crest cells from the far end of the neural crest (called
enteric cells) migrate to the intestine and are responsible
for ennervating the colon. Normal melanocyte and enteric neural crest
cell migration depends on the presence of endolethin B and endolethin
B receptors, which regulate the differentiation, proliferation, and
migration of melanocytes and enteric neural crest cells during
development.

Many mutations may affect this progess.

Spotting lethal, a mutation in the endolethin-B
receptor: A deletion in the gene for the endolethin-B
receptor, (a mutation called called spotting lethal (sl))
leads to problems in melanocyte and enteric cell dispersal in rats.
This leads to depigmentation of the forehead (blaze) and lack of
neural connection to the colon, which means the bowel cannot be
evacuated. Inability to evacuate the bowel is a condition called
megacolon or megacecum, and it is fatal (Dembowski et al.
2000, Tsaur et al. 1997, Kunieda et al. 1996, Gariepy
1996, Won et al. 2002).

Sl = normal

sl = spotting lethal

Note: mice have a comparable mutation affecting Endolethin
B, called piebald spotting (s). They also have a
separate mutation that knocks out Endolethin 3, with similar effects.
Confusingly, this Endolethin 3 mutation in mice is called lethal
spotting (ls), which is different from spotting lethal
(sl) in the rat. Whoever named these mutations needs to have his head
examined.

For more on the endolethin-B receptor and megacolon in mice, see
Zhu et al. 2004, and for more on mouse models of Waardenburg
syndrome, see Tachibana et al. 2003.

White spotting, a mutation in the Kit protein:A separate mutation, called white spotting (Ws) knocks
out the Kit protein, a tyrosine kinase transmembrane receptor,
which is produced by the c-kit gene. The mutation is a 12-base
deletion in the c-kit gene (Tsujimura et al. 1991). The kit
protein has a wide variety of functions! Kit is involved in the
development of blood stem cells (precursors to red and white blood
cells), melanoblasts, and primordial germ cells, and melanoblast
migration (Horie et al. 1991). So knocking out the kit protein
will have a variety of effects, including: depigmentation of certain
areas (up to and including entirely white with black eyes), and
sometimes anemia, a deficiency of mast cells (and therefore
deficiencies in histamine and serotonin), reproductive problems and
deafness (Kitamura et al. 1994, Hoshino 2000, Sugimoto
1995).

These aren't the only roles of the Kit protein, however. Kit is
also used in intestinal contractions: Special cells in the intestine
wall, called intersticial cells of Cajal (ICC) generate electrical
slow waves in the gastrointestinal tract. These slow waves regulate
the frequency of intestinal muscle contractions, so ICC are critical
for normal motility of the small intestine. ICC synthesize Kit, the
product of c-kit. Rats with the white spotting mutation don't produce
Kit in their intestines, and don't show electrical slow waves. This
results in abnormal contraction and megacolon (Takeda et al.
2001).

Ws = white spotting

ws = normal

Note:White spotting (Ws) in the rat is similar, but
not identical, to white spotting (W) in the mouse. Both are
mutations in the c-kit gene.

Examples: megacolon is known to be
occasionally associated with blazing in rats. Some blazed lines, such
as husky (depigmented foreheads and sides, sometimes odd-eyed)
may have higher incidence of megacolon.

Note, however, that megacolon may be caused by other factors as
well (e.g. a separate strain of congenital megacolon of unknown
cause, Lipman et al. 1998), that not all blazes are caused by
the spotted lethal or white spotting genes, and that not all
blazed/depigminted rats have megacolon!

Humans and other species: Humans have mutations in
pigment cell migration too, called Waardenburg syndrome. There are
many types of Waardenburg syndrome, each caused by a mutation in
different gene (PAX3, MITF, EDNRB, EDN3 and SOX10). The most severe
form of Waardenburg syndrome, called Waardenburg Type 4 or
Waardenbug-Shah, includes depigmentation, eye-color anomalies, and
megacolon (megacolon is called Hirschprung's disease in humans).

The Kit gene is implicated in the white color of some dog
breeds, where it is called spotting (s).
Spotting has several alleles in dogs. The dominant form
(S) produces a solid coat, sometimes with a little white
around the toes, chest and belly. The Irish spotting s(i)
allele produces white markings on the foreface, neck, lower limbs,
chest and belly (e.g. Boston Terrier and Basenji). In these animals,
pigment cells never make it to the colonizing sites on the neck
(Cattanach 1999).

The piebald spotting gene s(p) produces a wider
distribution of white (Cocker spaniels, Pointers). The most extreme
allele, s(w) is found in Dalmatians, English Setters, white
Bull Terriers, and white Boxers, where it produces a white coat,
sometimes with pigmented spots. In these animals, most of the coat is
depigemented, but a few pigment cells may make it to the colonizing
sites (notably around the eyes and ears), which proliferate and
produce dark spots (Cattanach 1999).

This extreme s(w) allele is responsible for the high
incidence of deafness in Dalmatians (20-30% of Dalmatians are hearing
impaired -- bilaterally or unilaterally deaf). Note, however, that
Dalmatians with colored patches on their ears have a lower incidence
of deafness, which indicates that if pigment cells make it to the ear
hearing tends to be normal (unfortunately, patches are considered a
fault in Dalmatians, so breeders breed against patches, and hence are
inadvertently selecting for deafness -- bummer for the dogs).
Interestingly, Boston Terriers are allowed to have head patches, and
they have a lower incidence of deafness (Cattanach 1999).

A mutation in the Kit gene is also responsible for the color
pattern of Hereford cattle, but is not associated with deafness.
Note, however, that Hereford cattle all have pigmented ears.

Mutations in melanosome
formation

A problem in the lineage of
cells leading to melanosomes: the red eyed dilution
allele

Melanosomes are tiny little vesicles found inside the
pigment cell. Pigments are assembled inside these little melanosomes,
which are then transported to the edge of the pigment cell and
deposit their pigment in the growing hair.

Melanosomes are actually part of a family of related "cell organs"
(organelles) (Orlow 1995, 1998), that includes
lysosomes and platelet dense granules. Lysosomes are
little vesicles inside cells that contain enzymes involved in
breaking down metabolites (waste). Platelet dense granules are found
in blood platelets (they store and secrete adenosine nucleotides and
serotonin). Defects in platelet dense granules lead to poor blood
clotting and prolonged bleeding.

These three kinds of organelles, melanosomes, lysosomes, and
platelet dense granules, all descend from a common ancestor
organelle. Therefore, any mutation that affects this common ancestor
will affect the descendants. The recessive red-eyed dilution
mutation (r) has just this effect.

The red-eyed dilution mutation interferes with normal development
of these organelles. This leads to abnormal transport of melanosomes
within the pigment cell, which causes reduced pigment deposit in the
hair and eyed -- hence the red eyes and pale fur. Homozygous rats
with red-eyed dilution also have abnormal platelet function,
called Platelet Storage Pool Deficiency (SPD) (LaVail 1981, Prieur
1984). In rats with SPD, platelets have defective secretion of
clotting mediators, which leads to profuse bleeding (Raymond and
Dodds 1975, Tschopp and Baumgartner 1977, Kirchmeier et al.
1990, Magro et al. 1992).

Red-eyed dilution is quite different from pink-eyed
dilution, thoug the animals may have a similar appearance (though
rr rats have reddish-brown eyes, while pp rats have
truly pink eyes (LaVail 1981)). Genetically, however, these are quite
distinct mutations that have very different effects.

Examples: An otherwise agouti rat homozygous for
red-eyed dilution will be a golden tan called fawn (Prieur
1984)

Note: The red-eyed dilution of agouti isn't the only way to
get a fawn colored rat. There is also a separate fawn mutation
(f), which reduces pigmentation in both black and blue animals,
though its cellular mechanism is unknown. Fawn on a black rat
produces a coffee brown animal, while fawn on a blue animal
produces a fawn animal (Castle and King 1947).

Other effects: Fawn (rr on agouti) hooded
rats are used extensively in research, and have a whole list of
associated disorders:

Fawn hooded rats have been used as an animal model for human
psychiatric disorders involving anomalies in serotonin function, such
as:

depression (Overstreet et al. 1992, Rezvani et al.
2002)

anxiety (Altemus 1994)

obsessive-compulsive disorder

eating disorders

Only the platelet storage disorder discussed above, and a
serotonin uptake disorder (Tobach et al. 1984) have been shown
to be caused by the red-eyed dilution gene (Hamada 1997, Fugimori
et al. 1998, Prieur 1984). Many of these other disorders may
be caused by other genes, which have come to be associated with these
laboratory lineages of fawn rats (Overstreet and Rezvani 1996,
Overstreet et al. 1999, Rezvani et al. 2002).

Human analogues:There are at least 15 mouse
analogues, including: light ear, maroon, pallid, pearl, and
ruby-eyed. Like red-eyed dilution, these analogous mutations affect
melanosomes, platelet storage granules, and lysosomes. However, none
of these analogous mutations are exactly the same mutation as
red-eyed dilution. In other words, these analogues affect the same
process but in different ways (Nguyen et al. 2002, Prieur
1984).

There are several human analogues that show platelet storage
deficiency and depigmentation:

Hermansky-Pudlak syndrome (HPS). Individuals with HPS have
a range of depigmentation, from white hair and skin to brown hair and
skin due to many freckles. Individuals with HPS have decreased visual
acuity and lung problems (pulmonary fibrosis) and intestinal problems
(granulomatous colitis). HPS is caused by a problem in the membrane
proteins of the three organelles mentioned above (melanosomes,
lysosomes, and platelet storage granules) which result in defective
transport. There are at least three different types of HPS (Huizing
and Gahl 2002). It is rare in most human populations, but is the most
common type of albinism in Puerto Rico. The mouse homologue of HPS is
pale ear.

Chediak-Higashi syndrome (CHS). Humans with CHS show
profound depigmentation of skin, severe recurrent infections,
proliferation of lymphoid tissue (lymphoproliferative disorder) and
numbness of the extremeties (progressive peripheral neuropathy).
Individuals with CHS have giant melanosomes in their melanocytes and
giant lysosomes in their white blood cells (leucocytes). This is a
serious condition and many people with CHS die prematurely. CHS is
also found in mink, cattle, mice and cats. The mouse homologue of CHS
is beige. There is also at least one instance in the
literature of beige rats with CHS symptoms (Ozaki et al.
1998).

I. Switching between light
and dark on a single hair: black and the agouti
gene

Melanocytes produce two types of pigment, brown-black eumelanins
and red-yellow phaeomelanins. The relative proportions of these
pigments are regulated by:

(1) alpha-MSH, which binds to a melanocortin receptor called MCR1
on melanocytes and stimulates them to produce brown-black eumelanins
by stimulating the production of tyrosinase, and

(2) the Agouti protein, which inhibits MSH from binding to MCR1
and results in the production of red-yellow phaeomelanins (Lu et
al. 1994).

Agouti has a separate avenue of action as well: Agouti inhibits
melanogenesis and generally reduces the synthesis of both pigments
(Graham et al. 1997).

A = aguoti

a = non-agouti

So, rats with the agouti protein alternate between brown-black and
red-yellow pigment production, producing banded hairs, which is the
wild-type phenotype of the Norway rat. Rats without the agouti
protein do not alternate. They produce eumelanins continuously and
their hairs are the same dark color the length of the shaft.

Examples: Rats with aa have solid hairs (with
no other modifiers, these are black rats), rats with A
have banded hairs, called agouti.

Other effects: Agouti protein also prevents MSH from
binding to its melanocortin receptors on neural cells (Lu et al.
1994, Willard et al. 1995). These melanocortins are potent
neuromodulators that have diverse effects on mammal behavior and
physiology, such that non-agouti rats are calmer and easier to handle
than agouti rats (Keeler 1942, Cottle and Price 1987). The behavioral
differences between agouti and nonagouti rats are probably due to the
regulation of MSH and its effects on the brain and subsequent
behavior.

The agouti gene therefore has an impact on behavior and may have
been important in the domestication of the
rat. Eighty percent of domestic laboratory rat strains are
homozygous for the nonagouti allele (see Price 2002 p. 16-17 for a
discussion).

An additional side effect occurs in a mutant with over-expression
of agouti in mice. Agouti binds to neural melanocortin-4 receptors
(MC4) in the brain, which are involved in food intake and homeostasis
(Skuladottir 1999). Mice with over-expression of Agouti are yellow
(from exclusive production of phaeomelanins) and obese from increased
food intake.

Human analogues: Humans have an agouti
analogue called agouti signal protein, ASIP, but its role is poorly
defined. It is expressed most in adipose (fat) tissue where it may
antagonize one of the melnocortin receptors. It may play a role in
energy homeostasis and and possibly human pigmentation (Voisey &
Daal 2002).

More interesting stuff about the MCR1-MSH... as you might
expect, a mutation in the MCR1 receptor would have interesting
consequences for pigmentation. MCR1 binds MSH, which causes the
production of dark eumelanin. With a non-functional MCR1, MSH can't
bind, and the melanosomes produces only light, yellow or red
phaeomelanins. Mutations in extension, the gene that codes for
MCR1, are not found in rats. But they are found in lots of other
species, such as mice, which produces a yellow coat color (in mice,
extension is called yellow (e)) (Robbins et
al. 1993). Extension mutations in the horse produce the
chestnut color (Marklund et al. 1996). Extension is
also found in red foxes, and in dogs such as yellow labradors, golden
retrievers, and Irish setters (Newton et al 2000; Everts et
al. 2000).

Other mutations in MCR1 cause it to be hyperactive, binding MSH
all the time and leading to the continuous production of dark
eumelanin. The black of black panthers is caused by such a mutation
(Robbins et al. 1993), as is the black of black sheep (Vage
et al. 1999). Hyperactive MSH mutations are found in mice too,
in the form of somber and tobacco darkening alleles
(Robbins et al. 1993).

MCR1 varies seasonally in some species, which is what causes the
transition from pale winter coats to dark spring and summer coats in
some animals.

In humans, mutations in the MCR1 receptors cause melanocytes to
synthesize red-yellow phaeomelanin, which produces red hair. There
are 6 known mutations in MCR1 which vary in how much they knock out
MCR1's function. Red-haired individuals are usually homozygotes or
compound heterozygoes (posessing two different types of MCR1
mutation). Two alleles for non-functional MCR1 will produce bright
red hair. People with just one mutated MCR1 allele, or alleles that
only partly impair MCR1's function, may show varying shades of red,
or no red at all. About 50% of white people carry a mutated MCR1,
which is thought to be significantly associated with fair skin even
if it does not produce red hair (Ha and Rees 2001, Rees 2000,
Schaffer and Bologna 2001).

As it turns out, phaeomelanins aren't as good at protecting the
skin from ultraviolet rays as eumelanins are, which is why red-headed
people are more prone to skin cancer.

II. Less pigment
deposited in the hair results in a lighter coat: the dilute
gene

Once the pigments are made, they have to be transported to the
hair. The pigment particles, called granules, are synthesized in
little vesicles called melanosomes, which are transported via the
dendrites of the melanocyte to the shaft of the growing hair. The
transport is actually really neat... melanosomes are carried by
little molecular feet (myosin 5, an actin dependent motor protein)
along little branching molecular "ladders" (actin filaments)
contained in projections off the melanocyte (dendrites) to the cell's
edge. If this transportation system is affected, transport to the
cell edge isn't normal.

Rats with the dilute mutation (called Myo5a(d) in the literature)
produce normal types and quantities of pigment in their melanocytes,
but the transport of these pigments to the hair shaft is disrupted
due to a mutation in myosin 5. Many melanosomes with their pigments
are stuck in the cell center, unable to be transported out to the
cell edge. So less pigment is incorporated in the hair, and when it
is incorporated it tends to be deposited in clumps. This gives the
coat a washed out, diluted color (Wu et al. 1998, Wei et
al. 1997).

d (also called MyoVa, Myo5a) = dilute

D = normal

There are several alleles of the dilute gene, such as dilute
lethal and dilute opisthotonus (dop), which result in severe
neurological defects (ataxia, seizures) and sometimes death in the
homozygous state (Futaki et al. 2000; Ohno et al.,
1996; Dekker-Ohno 1993).

Examples: Rats which are genetically black
but have the dilute mutation are a slate grey called blue.

Note, however, that there are many different mutations that give
rise to blue
rats in the pet rat fancy, so it is not clear which pet rat
mutation (if any) corresponds to the known mutation in MyoVa in
laboratory rats. Also note that the names of the different shades of
blue in pet rats and the Mendelian notations used to designate them
among rat breeders may differ between pet rat organizations and
countries.

Other effects: Pigment transport isn't the
only thing affected when myosin 5 is impaired. Myosin 5 is also used
in the elaboration and maintenance of cellular processes of the
melanocytes: homozygous d rats have melanocytes with fewer and
thinner dendritic processes. Myosin 5 is also responsible for
dragging endoplasmic reticulum (ER) to the cell edge of Purkinje
cells (large, important neurons in the brain) where it produces
calcium fluxes. If myosin 5 is disrupted, it can't drag ER to the
cell edge, calcium fluxes are disrupted, which reduces the Purkinje
cell's excitability, which results in neurological deficits as seen
in some of the more severe dilute mutations (see Tab et al. 1998;
Takagishi 1998; Hurvitz et al. 1993).

Human analogues: The human counterpart of the dilute
mutation is found in Griscelli Prunieras syndrome, a rare autosomal
recessive disease (Westbroek et al 2001). There are two types.
Individuals with Griscelli type 1 have a mutation in myosin 5 and are
characterized by partial albinism, silver-blond hair discoloration,
and neurological deficits. Individuals with Griscelli type 2 have a
mutation in another transport protein, called Rab27a, and they have
the symptoms of type 1 plus primary immunodeficiency (Klein et
al. 1994). Melanocytes of people with Griscelli symdromes have
short, stubby dendrites, and contain mature melanosomes, indicating a
transfer block toward the surrounding keratinocytes.

One of the earliest mutations in the pigment production pathway is
a mutation in the enzyme tyrosinase, which converts the
pigment precursor tyrosine into the next step. The gene for
tyrosinase is named chinchilla. If a mutation in the
chinchilla gene results in a completely nonfunctional tyrosinase
enzyme, then the animal will be unable to produce any pigment
anywhere in the body. Animals with this mutation are called
albinos.

The chinchilla gene has other known mutations, however, and many
of them result in a semi-functional tyrosinase. These produce animals
with diluted color compared to those with normal tyrosinase. In the
acromelanic version, the semi-functional tyrosinase is very fragile
and temperature dependent. Raise the temperature too much and the
tyrosinase breaks. Rats and other animals with temperature-sensitive
tyrosinase only produce pigment in the cooler areas of their bodies:
the extremeties such as nose, ears, feet and tail. Animals with these
temperature-sensitive mutations are siamese or
himalayan. For a specific molecular description of how the
tyrosinase produced by the achromelanic mutation differs from the
normal tyrosinase, see Kwon et al. 1989.

Here are some of the mutations in the chinchilla gene for
tyrosinase:

C = full color

C(ch) = Chinchilla

c(h) = Acromelanism (siamese)

c = Albino

Examples:C(ch)C(ch) produces
chinchilla, but this is (as far as I know) unheard of in rats.
Rats with cc are albino, and c(h)c(h) rats are
known as siamese. The combination c(h)c produces
pigmentation intermediate between albino and siamese and is known as
himalayan.

Other effects:lack of melanin pigment in the eye
and optic nerves leads to abnormal development and function, and
hence poor vision and sometimes blindness (Balkema and Drager 1991).
Absence of the fovea, nystagmus, strabismus, and reduced visual
acuity are common in all types of albinism. For more on how albino
rats see the world, see article entitled "what
do rats see?"

Human analogues:albinism occurs in humans, too,
where it is called oculocutaneous albinism type 1 (OCA1). There are
about 60 mutations that affect the the tyrosinase gene in humans
(Oetting & King 1993, Spritz 1994). How much pigment individuals
produce depends on how impared the tyrosinase enzyme is -- pigment
expression can range from completely absent (white skin, white hair,
and depigmented eyes) to nearly normal.

Pigment synthesis occurs in melanosomes: Tyrosine enters the
melanosome and the enzyme tyrosinase catalyzes it into dopaquinone.
Later on, down the eumelanin pathway, tyrosinase-related-proteins
turn brown pigment into black eumelanins. These chemical reactions
can be enhanced or impaired by changes in the internal pH of the
melanosome.

The p locus codes for a protein located on the
eumelanosome's membrane, a gate (transporter protein) that lets
molecules into the cell. The gate appears to help regulate the pH of
the melanosome by letting anions in (a different gate admits H+). A
mutation in the p locus affects this gate, changing the
normal, acidic pH to a more neutral environment. As p proteins
are not found on phaeomelanosomes, phaeomelanin production is not
affected by mutations in p.

An acidic environment in the melanosome is required for normal
tyrosinase activity (Brilliant et al. 2001. Strum 2001. Puri
et al. 2000). When melanosomes are acidic, they produce more
pigment, with a preferential increase in the dark eumelanins. When
they are neutral, they produce less eumelanin, but phaeomelanin is
relatively unaffected (Brilliant 2001). There is also some question
of the p gene being a tyrosine transporter (Rinchik 1993), but
the evidence is mixed.

So the p allele dilutes whatever color it is found with, by
reducing black-brown pigments and leaving the red-yellows alone. The
net result, in rats, is reduction in the dark eumelanin pigments,
resulting in a pale coat and pink eyes.

The p mutation has been found to be a deletion including
exons 17 and 18. It is an old mutation that is shared between a
number of laboratory rat strains (Kuramoto et al. 2005.)

P = normal pigmentation

p = pink-eyed dilute

Examples: in the agouti rat, the pink-eyed dilution
dilutes the dark band on each hair to a pale color, resulting in an
overall combination sometimes called amber. Straight black is
diluted to a pale yellow which is sometimes called
champagne.

The strong effect of the rat's pink-eye dilution p mutation
has its human analog in oculocutaneous albinism type 2, (OCA2). OCA 2
is the most common type of albinism in humans, especially among
people of African descent. Characeristics are highly variable,
however, ranging from minimal to moderate pigmentation of the hair,
skin, and iris. The pigment may be localized in freckles. Individuals
of African descent with OCA2 tend to have yellow hair, white skin
with localized pigment regions, and irises that are partially or
completely pigmented with a tan melanin. The p gene in humans
is located on a segment of chromosome 15, which is deleted in people
with Prader-Willi and Angelman syndromes, which may explain why
individuals with these syndromes have hypopigmented hair, eyes and
skin (Rinchik et al. 1993, Brilliant et al. 1994).

III. A last step in pigment
production that doesn't happen: the brown
mutation

After dopaquinone, the pigment pathway splits into two. One branch
leads to eumelanin and the other leads to phaeomelanin. One of the
mutations that affects the production of eumelanin is a mutation in
the brown gene, which codes for the enzyme TYRP1, which
catalyzes the final step of eumelanin synthesis: converting brown
pigment to black. With normal TYRP1, the final step takes place and
the animals produce black eumelanin. A mutation in TYRP1 means this
final step cannot happen, and animals with this mutation produce
brown eumelanin. There are at least two types of TYRP1 mutations: one
is a point mutation in TYRP1 which renders it non-functional, the
other is a mutation elsewhere that causes TYRP1 to be produced in low
quantities.

B = black

b = brown (also known as TYRP1(b))

Examples: Rats homozygous for the brown mutation are
called chocolate, in dogs this is often called liver.
Agouti rats homozygous for brown have brown instead of black
eumelanin stripes on their hairs, and are sometimes called
chocolate agouti.

Human analogues: mutations in TYRP1 are found
in humans, too, where they produces oculocutaneous albinism type 3
(OCA3). In humans as in mice and rats, TYRP1 catalyzes eumelanin
synthesis, but in humans it may have additional roles, such as
maintaining the stability of tyrosinase and modulating its activity.
It also maintainins melanosome structure and affects melanocyte
proliferation and cell death (Sarangarajan & Boissy 2001,
Sarangarajan et al. 2000).

Oculocutaneous albinism Type 3, also known as rufous
oculocutaneous albinism, xanthism, or xanthous albinism, is a common
autosomal disorder found in blacks (Manga 1997). People with rufous
albinism produce normal phaeomelanins (reds and yellows) but do not
produce the black eumelanins, only the brown ones. The first
description of a person with xanthous albinism was of an
African-American twin boy who had light brown skin, light brown hair,
and blue/gray irises while his fraternal twin had normal
pigmentation. More individuals have been described since then, such
individuals have a red to reddish brown coloration of the skin and
hair and reddish brown, slightly translucent irises; photophobia and
nystagmus are mild and visual acuity is normal or nearly normal.